PROJECT SUMMARY/ABSTRACT Allogeneic hematopoietic stem cell transplant (allo-HSCT) remains the only curative therapy for many patients with hematologic malignancies and marrow failure states. Key obstacles to the success of HSCT include collecting optimal numbers of hematopoietic stem/progenitor cells (HSPCs) capable of multilineage and durable engraftment, control of graft-versus-host disease (GvHD), and treating disease recurrence both before and especially after HSCT. I have focused my career over the last 20 years on overcoming these three obstacles to HSCT through the use of a bench-to-bedside and back again research approach. My research program over the next seven years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to (1) develop novel methods to target the hematopoietic niche for optimal HSPC mobilization and chemosensitization of acute myeloid leukemia (AML), (2) target the interferon gamma receptor (IFN?R) and IL-6R signaling pathways via use of selective and balanced JAK1/2 inhibitors to mitigate GvHD while maintaining graft vs. leukemia (GvL) after allo-HSCT, and (3) design and test novel AML and T cell acute lymphoblastic leukemia (T-ALL) immunotherapeutics. Successful HSCT requires the infusion of a sufficient number of HSPCs that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely fashion. In our first research area, we will use new strategies to enhance HSPC mobilization and leukemia chemosensitization via targeted modulation of the CXCR4/CXCL12, VLA-4/VCAM-1 and/or CXCR2/Gro-? axes. Managing the threat of GvHD while maximizing the beneficial GvL effect would broaden the scope and usefulness of allo-HSCT. In our second major research area we will perform preclinical and clinical studies to determine if targeting IFN?R, IL-6R, and/or JAK1/JAK2 can mitigate GvHD while maintaining GvL after T cell replete allo-HSCT. Finally, since many patients with AML die from progressive disease after relapse, our third research area will develop and translate into early phase clinical trials novel bi- and tri-specific monoclonal antibody reagents for the treatment of AML relapse before and after HSCT. We will complete ?first-in-man? phase I clinical trials of MGD006, a CD123xCD3 Dual Affinity Re-Targeting (DART) bispecific antibody-based molecule and AMV564, a CD33xCD3 Tandem Diabody, in patients with relapsed/refractory AML. While these trials are ongoing we are identifying novel targets for immunotherapy in AML and testing the efficacy of new retargeting agents that engage either T cells, NK cells or other immune effector cells to kill AML blasts expressing CD123, CD33, or the novel targets. Finally, since no targeted therapies currently exist for T-ALL, we are developing allogeneic chimeric antigen receptor T cells (CAR-T) to CD7, a T and NK cell marker that is highly expressed in T cell malignancies and in up to 40% of AML cases. To prevent normal T cell fratricide and alloreactivity, we are using the CRISPR/Cas-9 system to delete CD7 and the TCR? chain from donor T cells prior to transduction with the CD7 CAR.